A key step in advancing psychiatric medicine is to more fully elucidate the neural circuits responsible for specific domains of function that are commonly disrupted in mental disorders. Clarification of these circuit- function relationships will facilitate the development of pathophysiologically-based diagnostic and treatment strategies. The ventromedial sector of prefrontal cortex (vmPFC) is a crucial brain area in this regard. Abnormalities in vmPFC function and structure have been identified in virtually all mood and anxiety disorders, suggesting that vmPFC underlies some critical domain (or domains) of affective function that cut across traditional diagnostic categories. Yet the precise mechanisms by which vmPFC contributes to affective psychopathology remain unclear. The predominant neural circuitry model proposes that vmPFC regulates negative affect via top-down inhibition of brain areas involved in processing negative emotion-particularly the amygdala and insula-and that the pathologically elevated levels of negative affect characterizing mood and anxiety disorders result from a defect in this vmPFC-mediated inhibition of amygdala and insula activity. Three distinct mechanisms of vmPFC action have been proposed: (1) regulation of amygdala and insula activity in response to emotionally aversive stimuli, (2) regulation of amygdala and insula activity during the anticipation of emotionally aversive stimuli, and (3) regulation of amygdala activity during the extinction of conditioned fear. To date, empirical support for this model has largely been derived from two sources: animal fear conditioning studies (which cannot address the uniquely human psychological processes related to negative affect) and human fMRI studies of normal or psychiatric patient populations (which cannot address whether vmPFC dysfunction actually causes dysregulated amygdala or insula activity). Using an innovative approach-fMRI in neurological patients with discrete vmPFC lesions-this study will be the first to determine whether vmPFC is in fact necessary for regulating the activity of the amygdala and insula during affective processing in humans. We will examine amygdala and insula activity during each of the three fundamental aspects of affective processing described above, corresponding to three Specific Aims. Furthermore, in order to directly test the clinical relevance of this novel approach, each aim will also include a group of anxiety disorder patients. The direct comparison of fMRI results between vmPFC lesion patients and anxiety disorder patients will definitively establish whether the predominant theory-which holds that pathological levels of negative affect result from elevated amygdala and insula activity due to deficient top-down regulation by vmPFC-is indeed a viable neuropsychological model for mood and anxiety disorders. The study results will thus fill a major knowledge gap regarding the psychological and neurobiological mechanisms by which vmPFC modulates negative affect in humans, and significantly advance a program of research aimed at identifying neural circuit-level substrates of specific domains of affective function that are relevant to mental illness.